Raludotatug Deruxtecan Promising in Platinum-Resistant Advanced Ovarian Cancer

SAN DIEGO — Treatment with raludotatug deruxtecan (R-DXd) led to an “exciting” response rate among patients with heavily pretreated, platinum-resistant advanced ovarian cancer, according to an early-phase trial.

In a subgroup analysis of the first-in-human phase I study, there was one complete response and 17 partial responses among 37 evaluable patients treated with R-DXd, an antibody drug conjugate (ADC) directed against cadherin 6 (CDH6). The overall response rate was 48.6%, reported Kathleen Moore, MD, of the Stephenson Cancer Center at the University of Oklahoma in Oklahoma City.

The disease control rate was 97.4%, the median duration of response was 11.2 months, the time to response was 5.7 weeks, and the median progression-free survival was 8.1 months.

“R-DXd is the first ADC-targeting CDH6 to demonstrate promising signals of efficacy in ovarian cancer,” Moore said during a presentation at the Society of Gynecologic Oncology (SGO) annual meeting.

Carol Aghajanian, MD, of Memorial Sloan Kettering Cancer Center in New York City, called the response rate of nearly 50% “incredibly exciting.”

“This is an unmet medical need, and what I really liked about this paper is that it was really a representative population,” she said, noting that more than half of the patients in the trial were ages 65 and older.

“We see the rate of ovarian cancer declining in the United States each year, largely and probably due to BRCA1/2 testing, cascade testing, and risk-reducing surgeries, and we are going to be seeing more and more patients with more advanced age, and platinum-resistant disease, as we go forward,” noted Aghajanian, who was not involved in the study.

CDH6 is a transmembrane protein that is highly overexpressed in epithelial ovarian cancer (65%-85% of patients), making it a promising target for this ADC. R-DXd is composed of three parts — a humanized anti-CDH6 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload through a tetrapeptide-based cleavable linker.

The trial included patients with advanced epithelial ovarian cancer who had received prior taxane and platinum therapies. Median patient age was 66, and 88.9% had platinum-resistant disease. They had received a median of four prior regimens, with 64.4% having received bevacizumab, and 64.4% a PARP inhibitor.

Part A of the trial assessed the tolerability of R-DXd at 1.6-9.6 mg/kg. Doses of 4.8-8.0 mg/kg were expanded in Part B, with the 8.0 mg/kg cohort eventually closed due to the risk-to-benefit ratio. The current subgroup analysis included patients who received R-DXd at 4.8-6.4 mg/kg. Trial findings through March 2023 were presented at the 2023 European Society for Medical Oncology meeting.

As of July 2023, 45 patients had received R-DXd at 4.8 (n=13), 5.6 (n=8), and 6.4 (n=24) mg/kg. At the data cutoff, 30 patients (66.7%) were still receiving study treatment, with a median treatment duration of 17.9 weeks.

Moore reported that a preliminary biomarker assessment showed R-DXd was active in tumors harboring a wide range of CDH6 expression, but that a correlation between CDH6 expression and response has yet to be observed.

Regarding safety, any-grade treatment-emergent adverse events (TEAEs) were experienced by 93.3% of patients, and grade ≥3 TEAEs were reported in 44.4% of patients.

The most common any-grade TEAEs were nausea (57.8%), vomiting (40.0%), fatigue (37.8%), and diarrhea (31.1%).

The most common hematologic AE was anemia at 26.7% (15.6% grades ≥3).

Drug-related interstitial lung disease/pneumonitis was reported in two patients who received a starting dose of 6.4 mg/kg, both of which were grade 2, and both of which resolved.

AEs led to R-DXd discontinuation in five patients (11.1%), dose interruption in 14 patients (31.1%), and dose reduction in seven patients (15.8%), “speaking to the well-tolerated nature of this agent,” Moore reported.

R-DXd will be further evaluated in patients with platinum-resistant ovarian cancer in the phase II/III REJOICE-Ovarian01 trial.

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